A tumor microenvironment-responsive core-shell tecto dendrimer nanoplatform for magnetic resonance imaging-guided and cuproptosis-promoted chemo-chemodynamic therapy

As a principal modality for cancer treatment, chemotherapy could induce the regulated death of tumor cells in different subroutines. However, the curative efficacy of chemotherapy is often limited due to the non-targeted delivery of anticancer drugs, the low drug bioavailability, the resistance of tumor cells to apoptosis by overexpressing anti-apoptotic proteins or the multi-drug resistance effect, and the limited efficacy of monotherapy modality [1]. To overcome those obstacles, combination therapy has emerged and shown lots of promise in cancer treatment [2,3]. Therefore, how to effectively combine multiple anticancer strategies into one tumor-targeting nanoplatform and realize the killing of tumor cells through different mechanisms synergistically has become a hot topic in biomedical research. Furthermore, it is also highly desirable if the nanoplatform can be multifunctional, for instance, achieving not only cancer treatment but also tumor diagnosis at the same time.

Poly(amidoamine) (PAMAM) dendrimers have been widely used to construct cancer diagnosis and treatment nanoplatforms due to their unique internal cavities, abundant peripheral functional groups for further modification, and excellent biocompatibility [4], [5], [6]. In recent years, the development of supramolecular chemistry technology along with dendrimer chemical modification has propelled the research of dendrimers in biomedical applications to a new stage. Core-shell tecto dendrimers could be built by the supramolecular self-assembly of surface-modified dendrimers, such as β-cyclodextrin(CD) and adamantine(Ad) modification, and exhibit controllable size, higher drug loading capacity [7], and better tumor permeability than simple dendrimers [8,9]. In addition, the introduction of responsive linkages in building core-shell tecto dendrimer might enable the specific dissociation in the tumor microenvironment (TME) and selective drug release for specific inhibition of tumors.

Herein, a responsive all-in-one nanoplatform was designed by assembling mannose and phenylboronic acid (PBA) modified dendrimers to form a core-shell tecto dendrimer (CSTD) based on phenylboronic ester bonds, which could be responsively broken in TME with low pH and high H2O2 [10], [11], [12]. In our design, copper Cu(II) ion was chosen as the key multifunctional agent to load into CSTD because of the following considerations. Firstly, copper is an essential metal element for humans, but recent research has demonstrated that excessive intracellular copper ions could be used as effective therapeutic agents and induce a new form of regulated cell death, termed cuproptosis [13]. Different from apoptosis and other known pathways, excessive copper ions could bind to lipoylation-related enzymes and promote their oligomerization, resulting in proteotoxic stress and cell death. Secondly, Cu(II) ions could be reduced by the excessive GSH in tumor cells and react with endogenous H2O2 to produce toxic •OH realizing chemodynamic therapy (CDT) in a TME-responsive manner. Further, Cu ions could also be a potential T1-weighted MR contrast agent due to the unpaired electrons in the outermost orbital [14,15]. Finally, it is known that owing to the abundant amino groups on PAMAM dendrimers, copper ions can be effectively loaded through complexation, as illustrated in our previous work [16,17]. All these factors make copper ion an attractive candidate for an active agent for the construction of a dendrimer-based combination antitumor treatment system, which may have the potential to overcome the current deficiency of conventional chemotherapy and generate synergistic mechanisms in cell death, and even enhance the contrast of tumors in MR imaging for theranostics.

To further boost the tumor inhibition effect of the nanosystem, we then introduced disulfiram (DSF) as a synergist to couple with the copper ion into our design. As an FDA-approved antialcoholism drug, DSF has recently been demonstrated to be an effective anticancer drug, especially for breast cancer [18]. DSF could induce ROS-dependent oxidative stress [19], and damage DNA [20] to suppress cancer cell proliferation. More importantly, when combined with copper ions, the two agents can work synergistically and even break drug resistance [21]. It is verified that DSF can be rapidly converted into diethyldithiocarbamate (DTC) in cells [22] and chelate with intracellular copper ions [23] to form Cu(DTC)2 complex [24,25], which is the decisive metabolite for tumor inhibition. Meanwhile, DSF can also act as a copper ion carrier to promote the uptake of copper ions by cells. For instance, Cen et al. demonstrated that DSF facilitated the intracellular Cu uptake in A375 melanoma cells by 4 times, leading to a significantly enhanced therapeutic effect [26]. Considering the rapid metabolism and poor accumulation of DSF and Cu2+ at tumor sites, loading the two agents together into a tumor-targeted TME-responsive drug delivery system would be of great significance for fully unleashing their combination therapy efficacy and reducing the toxic side effects.

In the present study, the TME-responsive core-shell teco dendrimer (CSTD) was constructed by the assembly of mannose-modified generation 5 (G5) poly(amidoamine) dendrimers (G5.NH2-Man, as shell) with PBA modified G5 (G5.NH2-PBA, as core) via the formation of phenylboronic ester bonds. The formed CSTD was expected to complex enormous Cu(II) owing to their huge amount of amino groups and load DSF efficiently by forming DSF/Cu complexes. The attaching of mannose on the surface renders CSTD targeted accumulation and specific uptake by tumors presenting galactines, and the effective release of drugs would be triggered in TME by the dissociation of CSTD. As a result, the integration of chemotherapy with cuproptosis and chemodynamic therapy would be achieved to efficiently suppress tumor growth in a specific and responsive manner, and meanwhile, the enhanced T1-weighted magnetic resonance imaging would be achieved. This study is the first report of an all-in-one tumor-targeted and TME-responsive CSTD nanoplatform for cuproptosis-promoted synergistic therapies and enhanced MR imaging. The promising results from this study would shed new light on the future design and development of multifunctional nanoplatforms for early accurate diagnosis and effective treatment of cancers.

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